LIAISON: Novel interaction of Kv channels across families

Voltage-gated potassium channels (Kv) are tetrameric assemblies that are important for a variety of cellular processes. A subset of them (Kv5, Kv6, Kv8 and Kv9) does not form functional channels when expressed alone (therefore termed silent Kv, KvS), but they can co-assemble to heteromers with another Kv isoform Kv2. This leads to differing channel properties as compared to homomeric Kv2 channels. The Kv2-KvS co-assembly is so far the only known example for heteromerization of subunits across Kv families. We could recently show that Kv7 subunits, which show high homology with KvS channels, colocalize in a common protein complex with KvS subunits in hippocampal neurons and photoreceptors, and that Kv7 currents are attenuated by pathogenic KvS mutations that might contribute to the development of epilepsy and retinopathy. Therefore, we hypothesize that also Kv7 and KvS heteromerize into functional Kv channels with pathophysiologicalimportance. Using a combination of biochemical, electrophysiological and imaging techniques we will investigate the Kv7-KvS interaction in expression systems both in vitro and in vivo, in novel genetically modified mouse lines. The project LIAISON will generate new data on the molecular principles underlying an unexpected interaction across Kv families, thereby challenging a central theorem on the formation of Kv channels. It is a collaborative research effort of laboratories of the Medical University of Innsbruck, Austria, and the Philipps-University Marburg, Germany.

Voltage-gated potassium channels (Kv) are tetrameric complexes that are responsible for a wide range of cellular processes. Some Kv isoforms do not form functional channels when expressed alone (silent Kv, KvS), but can assemble with other isoforms to form heteromeric channels with altered biophysical properties. In the present project, carried out in collaboration with research groups at Philipps-University Marburg, the molecular basis of an unexpected interaction between the Kv7 channel subunit and several members of the silent KvS family was investigated. The results demonstrate that silent KvS subunits can directly interact with Kv7 channels and substantially modify their electrical properties. Transcriptomic analyses indicate that this novel channel composition occurs in physiologically relevant cell types, including neurons of the hippocampus, sensory neurons of the dorsal root ganglia, and cardiac tissue. Together, these findings significantly expand the current understanding of the functional diversity of voltage-gated potassium channels.